Identification of a combination of transcription factors that synergistically increases endothelial cell barrier resistance
Endothelial cells (ECs) display remarkable plasticity during development before becoming quiescent and functionally mature. EC maturation is directed by several known transcription factors (TFs), but the specific set of TFs responsible for promoting high-resistance barriers, such as the blood-brain...
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| Veröffentlicht in: | Scientific reports 2020-03, Vol.10 (1), p.3886-3886, Article 3886 |
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| creator | Roudnicky, Filip Kim, Bo Kyoung Lan, Yanjun Schmucki, Roland Küppers, Verena Christensen, Klaus Graf, Martin Patsch, Christoph Burcin, Mark Meyer, Claas Aiko Westenskow, Peter D. Cowan, Chad A. |
| description | Endothelial cells (ECs) display remarkable plasticity during development before becoming quiescent and functionally mature. EC maturation is directed by several known transcription factors (TFs), but the specific set of TFs responsible for promoting high-resistance barriers, such as the blood-brain barrier (BBB), have not yet been fully defined. Using expression mRNA data from published studies on
ex vivo
ECs from the central nervous system (CNS), we predicted TFs that induce high-resistance barrier properties of ECs as in the BBB. We used our previously established method to generate ECs from human pluripotent stem cells (hPSCs), and then we overexpressed the candidate TFs in hPSC-ECs and measured barrier resistance and integrity using electric cell-substrate impedance sensing, trans-endothelial electrical resistance and FITC-dextran permeability assays. SOX18 and TAL1 were the strongest EC barrier-inducing TFs, upregulating Wnt-related signaling and EC junctional gene expression, respectively, and downregulating EC proliferation-related genes. These TFs were combined with SOX7 and ETS1 that together effectively induced EC barrier resistance, decreased paracellular transport and increased protein expression of tight junctions and induce mRNA expression of several genes involved in the formation of EC barrier and transport. Our data shows identification of a transcriptional network that controls barrier resistance in ECs. Collectively this data may lead to novel approaches for generation of
in vitro
models of the BBB. |
| doi_str_mv | 10.1038/s41598-020-60688-x |
| format | Article |
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ex vivo
ECs from the central nervous system (CNS), we predicted TFs that induce high-resistance barrier properties of ECs as in the BBB. We used our previously established method to generate ECs from human pluripotent stem cells (hPSCs), and then we overexpressed the candidate TFs in hPSC-ECs and measured barrier resistance and integrity using electric cell-substrate impedance sensing, trans-endothelial electrical resistance and FITC-dextran permeability assays. SOX18 and TAL1 were the strongest EC barrier-inducing TFs, upregulating Wnt-related signaling and EC junctional gene expression, respectively, and downregulating EC proliferation-related genes. These TFs were combined with SOX7 and ETS1 that together effectively induced EC barrier resistance, decreased paracellular transport and increased protein expression of tight junctions and induce mRNA expression of several genes involved in the formation of EC barrier and transport. Our data shows identification of a transcriptional network that controls barrier resistance in ECs. Collectively this data may lead to novel approaches for generation of
in vitro
models of the BBB.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-020-60688-x</identifier><identifier>PMID: 32127614</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/100 ; 13/106 ; 38 ; 38/90 ; 38/91 ; 42 ; 42/44 ; 631/136/16/1986 ; 631/532/1360 ; Blood-brain barrier ; Blood-Brain Barrier - cytology ; Cell Differentiation ; Central nervous system ; Developmental plasticity ; Dextran ; Endothelial cells ; Endothelial Cells - cytology ; Endothelial Cells - metabolism ; Ets-1 protein ; Gene expression ; Humanities and Social Sciences ; Humans ; Maturation ; multidisciplinary ; Permeability ; Pluripotency ; Pluripotent Stem Cells - cytology ; Protein transport ; Science ; Science (multidisciplinary) ; Stem cells ; Tight junctions ; Transcription factors ; Transcription Factors - metabolism ; Wnt protein</subject><ispartof>Scientific reports, 2020-03, Vol.10 (1), p.3886-3886, Article 3886</ispartof><rights>The Author(s) 2020</rights><rights>This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c511t-196ab317cf2d151b1850040ec9b879ad44e75c85463845273b8e3d3958aa78673</citedby><cites>FETCH-LOGICAL-c511t-196ab317cf2d151b1850040ec9b879ad44e75c85463845273b8e3d3958aa78673</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054428/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054428/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,41120,42189,51576,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32127614$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Roudnicky, Filip</creatorcontrib><creatorcontrib>Kim, Bo Kyoung</creatorcontrib><creatorcontrib>Lan, Yanjun</creatorcontrib><creatorcontrib>Schmucki, Roland</creatorcontrib><creatorcontrib>Küppers, Verena</creatorcontrib><creatorcontrib>Christensen, Klaus</creatorcontrib><creatorcontrib>Graf, Martin</creatorcontrib><creatorcontrib>Patsch, Christoph</creatorcontrib><creatorcontrib>Burcin, Mark</creatorcontrib><creatorcontrib>Meyer, Claas Aiko</creatorcontrib><creatorcontrib>Westenskow, Peter D.</creatorcontrib><creatorcontrib>Cowan, Chad A.</creatorcontrib><title>Identification of a combination of transcription factors that synergistically increases endothelial cell barrier resistance</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Endothelial cells (ECs) display remarkable plasticity during development before becoming quiescent and functionally mature. EC maturation is directed by several known transcription factors (TFs), but the specific set of TFs responsible for promoting high-resistance barriers, such as the blood-brain barrier (BBB), have not yet been fully defined. Using expression mRNA data from published studies on
ex vivo
ECs from the central nervous system (CNS), we predicted TFs that induce high-resistance barrier properties of ECs as in the BBB. We used our previously established method to generate ECs from human pluripotent stem cells (hPSCs), and then we overexpressed the candidate TFs in hPSC-ECs and measured barrier resistance and integrity using electric cell-substrate impedance sensing, trans-endothelial electrical resistance and FITC-dextran permeability assays. SOX18 and TAL1 were the strongest EC barrier-inducing TFs, upregulating Wnt-related signaling and EC junctional gene expression, respectively, and downregulating EC proliferation-related genes. These TFs were combined with SOX7 and ETS1 that together effectively induced EC barrier resistance, decreased paracellular transport and increased protein expression of tight junctions and induce mRNA expression of several genes involved in the formation of EC barrier and transport. Our data shows identification of a transcriptional network that controls barrier resistance in ECs. Collectively this data may lead to novel approaches for generation of
in vitro
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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Roudnicky, Filip</au><au>Kim, Bo Kyoung</au><au>Lan, Yanjun</au><au>Schmucki, Roland</au><au>Küppers, Verena</au><au>Christensen, Klaus</au><au>Graf, Martin</au><au>Patsch, Christoph</au><au>Burcin, Mark</au><au>Meyer, Claas Aiko</au><au>Westenskow, Peter D.</au><au>Cowan, Chad A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of a combination of transcription factors that synergistically increases endothelial cell barrier resistance</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2020-03-03</date><risdate>2020</risdate><volume>10</volume><issue>1</issue><spage>3886</spage><epage>3886</epage><pages>3886-3886</pages><artnum>3886</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Endothelial cells (ECs) display remarkable plasticity during development before becoming quiescent and functionally mature. EC maturation is directed by several known transcription factors (TFs), but the specific set of TFs responsible for promoting high-resistance barriers, such as the blood-brain barrier (BBB), have not yet been fully defined. Using expression mRNA data from published studies on
ex vivo
ECs from the central nervous system (CNS), we predicted TFs that induce high-resistance barrier properties of ECs as in the BBB. We used our previously established method to generate ECs from human pluripotent stem cells (hPSCs), and then we overexpressed the candidate TFs in hPSC-ECs and measured barrier resistance and integrity using electric cell-substrate impedance sensing, trans-endothelial electrical resistance and FITC-dextran permeability assays. SOX18 and TAL1 were the strongest EC barrier-inducing TFs, upregulating Wnt-related signaling and EC junctional gene expression, respectively, and downregulating EC proliferation-related genes. These TFs were combined with SOX7 and ETS1 that together effectively induced EC barrier resistance, decreased paracellular transport and increased protein expression of tight junctions and induce mRNA expression of several genes involved in the formation of EC barrier and transport. Our data shows identification of a transcriptional network that controls barrier resistance in ECs. Collectively this data may lead to novel approaches for generation of
in vitro
models of the BBB.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32127614</pmid><doi>10.1038/s41598-020-60688-x</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 13 13/100 13/106 38 38/90 38/91 42 42/44 631/136/16/1986 631/532/1360 Blood-brain barrier Blood-Brain Barrier - cytology Cell Differentiation Central nervous system Developmental plasticity Dextran Endothelial cells Endothelial Cells - cytology Endothelial Cells - metabolism Ets-1 protein Gene expression Humanities and Social Sciences Humans Maturation multidisciplinary Permeability Pluripotency Pluripotent Stem Cells - cytology Protein transport Science Science (multidisciplinary) Stem cells Tight junctions Transcription factors Transcription Factors - metabolism Wnt protein |
| title | Identification of a combination of transcription factors that synergistically increases endothelial cell barrier resistance |
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